6. A process for the preparation of crystalline form D of perindopril
erbumine according to claim 1 comprising steps of:(a1) suspending
perindopril erbumine in dichloromethane,(a2) heating the suspension up to
40.degree. C.,(a3) cooling down obtained solution slowly to 20-25.degree.
C. and,(a4) isolating said crystalline form.

7. A process for the preparation of crystalline form D of perindopril
erbumine according to claim 1 comprising steps of:(b1) suspending
perindopril erbumine in dichloromethane,(b2) heating the suspension up to
40.degree. C.,(b3) cooling down obtained solution in an ice-bath and,(b4)
isolating said crystalline form.

8. A process for the preparation of crystalline form D of perindopril
erbumine according to claim 1 comprising steps of:(c1) suspending
perindopril erbumine in acetonitrile,(c2) heating the suspension up to
70.degree. C.,(c3) cooling down obtained solution slowly to 20-25.degree.
C. and,(c4) isolating said crystalline form.

9. A process for the preparation of crystalline form D of perindopril
erbumine according to claim 1 comprising a lyophilization of 5%
perindopril erbumine solution in water.

10. A process for the preparation of crystalline form D of perindopril
erbumine according to claim 1 comprising steps of:(e1) moistening
perindopril erbumine with water and,(e2) drying obtained paste at
temperature from 20-25.degree. C. and a relative humidity below 40%.

11. A process for the preparation of crystalline form D of perindopril
erbumine according to claim 1 comprising steps of:(f1) suspending
perindopril erbumine in t-butylmethyl ether,(f2) adding sufficient amount
of water to induce dissolution,(f3) heating the suspension up to
40.degree. C.(f4) cooling down obtained solution slowly to 20-25.degree.
C. and,(f5) isolating said crystalline form.

12. A process for the preparation of crystalline form D of perindopril
erbumine according to claim 1 comprising steps of:(g1) suspending
perindopril erbumine in t-butylmethyl ether,(g2) adding sufficient amount
of water to induce dissolution,(g3) heating the suspension up to
40.degree. C.(g4) cooling down obtained solution quickly to about
5.degree. C. and,(g5) isolating said crystalline form.

13. Use of crystalline form D of perindopril erbumine according to claim 1
for the preparation of pure crystalline form α or any other known
crystalline form of perindopril erbumine.

14. A process for the preparation of pure crystalline form α or any
other known crystalline form of perindopril erbumine comprising a step of
preparing crystalline from D of perindopril erbumine according to claim
1.

15. A process according to claim 6, wherein in a further step the obtained
crystalline form D of perindopril erbumine is formulated into a
pharmaceutically acceptable dosage form, in particular wherein said
dosage form is a tablet, pill, capsule or injectable.

16. A pharmaceutical composition comprising crystalline form D of
perindopril erbumine according to claim 1.

17. Use of new crystalline form D of perindopril erbumine according to
claim 1 for the preparation of a pharmaceutical composition for use in
the treatment of cardiovascular diseases.

Description:

[0001]The present invention relates to new crystalline form of perindopril
erbumine.

[0002]Perindopril and its pharmaceutically acceptable salts are known as
angiotensin converting enzyme inhibitors and are used in the treatment of
cardiovascular diseases, especially in the treatment of hypertension and
heart failure. Perindopril is chemically known as
(2S,3aS,7aS)-((2-(1-(ethoxycarbonyl)-(S)-butylamino)-(S)-propionyl)octahy-
dro-indole-2-carboxylic acid and can be represented by formula (I).

##STR00001##

[0003]Perindopril was first disclosed in EP 0049658 B1 and U.S. Pat. No.
4,508,729 as optically pure S,S,S,S,S isomer and in the form of sodium
salt. Numerous later patents and patent applications, such as EP 0308341
B1, EP 1279665 A1, EP 1333026 A1, WO 2004/099236 describe various
processes for the preparation of perindopril.

[0004]Perindopril in a non-salted form is an oily, amorphous or hardly
crystalline material depending on a process for the preparation and
presence of impurities. In addition to the by-products formed during the
process of the preparation thereof, also degradation products of
perindopril, such as diketopiperazines and perindoprilate, are present as
impurities in crude perindopril.

[0005]Pharmaceutically acceptable compounds have to be obtained in high
purity and have to be stable for long periods. Additionally, it is
important that such compounds have valuable characteristics of isolation,
such as filtration and drying, to be produced at industrial scale.

[0006]Hitherto only tert-butylamine salt of perindopril, i.e. perindopril
erbumine, firstly disclosed in EP 0308341, has enough good crystalline
properties to be used for pharmaceutical purposes (i.e. having well
defined and stable physical properties). Perindopril erbumine may be
obtained in different crystalline forms depending on crystallization
conditions, e.g. solvent system, perindopril erbumine concentration and
cooling kinetic. EP 1296947 B1 discloses crystallization of perindopril
erbumine crystalline form α from ethyl acetate, EP 1294689 A
discloses crystallization of perindopril erbumine crystalline form β
from dichloromethane or ethyl acetate, EP 1296948 B1 discloses
crystallization of perindopril erbumine crystalline form γ from
chloroform and WO 2004/113293 discloses crystallization of perindopril
erbumine crystalline form δ and crystalline form ε.
Crystalline form ε is obtained by crystallization from tert-butyl
methyl ether containing 1.5 to 2.5% (vol/vol) of water. whereas
crystalline form δ is obtained from form ε by azeotropic
distillation.

[0007]However, there is a continuing need to obtain new crystalline form
of perindopril erbumine having improved characteristics in term of
isolation and purification.

[0008]A first object of the present invention is related to new
crystalline form of perindopril erbumine, named form D, having a powder
x-ray diffraction pattern comprising the following characteristic
reflection angles 2θ: 5.3±0.2°, 10.7±0.2°,
16.1±0.2°, 24.4±0.2° and 27.0±0.2°.

[0009]New crystalline form D of perindopril erbumine has a powder x-ray
diffraction pattern as depicted in FIG. 1 and shows the following
characteristic 2θ angles:

[0013]The Applicant has surprisingly found that new crystalline form D of
perindopril erbumine has valuable characteristic in term of isolation and
purification.

[0014]The new crystalline form D of perindopril erbumine according to the
invention is obtained in a higher purity compared to the crystalline form
α or any other known crystalline form of perindopril erbumine, when
both forms are prepared from the same crude perindopril and using the
same number of recrystallization steps.

[0015]Another object of the present invention is related to processes for
the preparation of new crystalline form of perindopril erbumine. New
crystalline form D of perindopril erbumine may be prepared from any other
crystalline form of perindopril erbumine or from solution of perindopril
erbumine.

[0016]In one embodiment, the present invention relates to a process (a)
for the preparation of new crystalline form D of perindopril erbumine
comprising the steps of: [0017](a1) suspending perindopril erbumine in
dichloromethane, [0018](a2) heating the suspension up to 40° C.,
[0019](a3) cooling down obtained solution slowly to 20-25° C.,
preferably at a rate of about 10° C./h and, [0020](a4) isolating
new crystalline form D, preferably by filtration under reduced pressure,
preferably at about 10 mbar, followed by drying.

[0021]In another embodiment, the present invention relates to a process
(b) for the preparation of new crystalline form D of perindopril erbumine
comprising the steps of: [0022](b1) suspending perindopril erbumine in
dichloromethane, [0023](b2) heating the suspension up to 40° C.,
[0024](b3) cooling down obtained solution in an ice-bath and, [0025](b4)
isolating new crystalline form D, preferably by filtration under reduced
pressure, preferably at about 10 mbar, followed by drying.

[0026]In another embodiment, the present invention relates to a process
(c) for the preparation of new crystalline form D of perindopril erbumine
comprising the steps of: [0027](c1) suspending perindopril erbumine in
acetonitrile, [0028](c2) heating the suspension up to 70° C.,
[0029](c3) cooling down obtained solution slowly to 20-25° C.,
preferably at a rate of about 10° C./h and, [0030](c4) isolating
new crystalline form D, preferably by filtration under reduced pressure,
preferably at about 10 mbar, followed by drying.

[0031]In another embodiment, the present invention relates to a process
(d) for the preparation of new crystalline form D of perindopril erbumine
comprising a lyophilization of about 5% perindopril erbumine solution in
water. For example, said solution is freezed with liquid nitrogen and
freeze drying is performed at -20° C. and at a pressure of about
0.2 mbar over three days.

[0032]In another embodiment, the present invention relates to a process
(e) for the preparation of new crystalline form D of perindopril erbumine
comprising the steps of: [0033](e1) moistening perindopril erbumine
with water and, [0034](e2) drying obtained paste at temperature from
20-25° C. and a relative humidity below 40%.

[0035]In another embodiment, the present invention relates to a process
(f) for the preparation of new crystalline form D of perindopril erbumine
comprising the steps of:

[0036](f1) suspending perindopril erbumine in t-butylmethyl ether,
[0037](f2) adding sufficient amount of water to induce dissolution, e.g.
about 1-5% (vol/vol) of water, preferably about 3% (vol/vol) of water is
added, [0038](f3) heating the suspension up to 40° C., [0039](f4)
cooling down obtained solution slowly to 20-25° C., preferably at
a rate of about 10° C./h and, [0040](f5) isolating new crystalline
form D, preferably by filtration under reduced pressure, preferably at
about 10 mbar, followed by drying.

[0041]In another embodiment, the present invention relates to a process
(g) for the preparation of new crystalline form D of perindopril erbumine
comprising the steps of: [0042](g1) suspending perindopril erbumine in
t-butylmethyl ether, [0043](g2) adding sufficient amount of water to
induce dissolution, e.g. about 1-5% (vol/vol) of water, preferably about
3% (vol/vol) of water is added, [0044](g3) heating the suspension up to
40° C., [0045](g4) cooling down obtained solution quickly to about
5° C. and, [0046](g5) isolating new crystalline form D, preferably
by filtration under reduced pressure, preferably at about 10 mbar,
followed by drying.

[0047]Another object of the present invention is related to any of the
processes as described above, wherein in a further step the new
crystalline form D of perindopril erbumine as obtained according to one
of the processes as described previously is formulated into a
pharmaceutically acceptable dosage form, in particular wherein said
dosage form is a tablet, pill, capsule or injectable.

[0048]Another object of the present invention is related to use of new
perindopril erbumine crystalline form D in the process for the
preparation of pure crystalline form α or any other known
crystalline form of perindopril erbumine.

[0049]Another object of the present invention is related to a process for
the preparation of pure crystalline form α or any other known
crystalline form of perindopril erbumine comprising a step of preparing
new crystalline form D of perindopril erbumine.

[0050]"Pure" crystalline form of perindopril erbumine in the present
invention means crystalline form of perindopril erbumine having more than
95%, preferably more than 99%, more preferably more than 99.5%, most
preferably more than 99.8%, of chromatographic purity.

[0051]Another object of the present invention is related to pharmaceutical
compositions comprising a therapeutically effective amount of new
crystalline form D of perindopril erbumine with one or more
pharmaceutically acceptable carriers or other excipients.

[0052]A therapeutically effective amount of perindopril salt is the amount
of perindopril salt which comprises an amount of perindopril which is
appropriate in a dosage form useful to treat hypertension or
cardiovascular diseases. In general, a pharmaceutically effective amount
of perindopril is 1 to 15 mg of perindopril, preferably 2 to 8 mg.

[0053]Pharmaceutically acceptable excipients may be selected from the
group consisting of binders, diluents, disintegrating agents, stabilizing
agents, preservatives, lubricants, fragrances, flavoring agents,
sweeteners and other excipients known in the field of the pharmaceutical
technology. Preferably, carriers and excipients may be selected from the
group consisting of hydroxypropylcellulose, lactose, microcrystalline
cellulose, calcium carbonate, starch, colloidal silicone dioxide, sodium
starch glycolate, talc, magnesium stearate, polyvinylpyrrolidone, and
other excipients known in the field of the pharmaceutical technology.

[0054]Optionally, the pharmaceutical compositions of the invention may be
combination products comprising one or more additional pharmaceutically
active components in addition to perindopril. Preferably, an additional
pharmaceutically active component is a diuretic, e.g. indapamide.

[0055]Suitable pharmaceutical compositions are solid dosage forms, such as
tablets with immediate release or sustained release of the active
principle, effervescent tablets or dispersion tablets and capsules.

[0056]The pharmaceutical compositions may be prepared by methods known in
the field of the pharmaceutical technology.

[0057]Another object of the present invention is related to the use of new
crystalline form D of perindopril erbumine for the preparation of a
pharmaceutical composition for use in the treatment of cardiovascular
diseases, e.g. hypertension or heart failure.

[0058]Another object of the present invention is related to a method for
the treatment of cardiovascular diseases, e.g. hypertension or heart
failure, comprising administering a therapeutically effective amount of
new crystalline form D of perindopril erbumine.

[0059]The following examples illustrate the invention, but do not limit it
in any way.

[0060]FIG. 1 depicts a powder x-ray diffraction pattern of new crystalline
form D of perindopril.

[0061]FIG. 2 depicts IR spectrum of new crystalline form D of perindopril.

[0062]FIG. 3 depicts Raman spectrum of new crystalline form D of
perindopril.

EXAMPLE 1

Preparation of Crystalline Form D of Perindopril Erbumine

[0063]0.25 g of perindopril erbumine form α are suspended in 5 ml of
dichloromethane and the suspension is heated up to 40° C. The
clear solution is cooled down to room-temperature at a rate of about
10K/h. The yield is filtered under reduced pressure (10 mbar) and
air-dried. Yield: 0.23 g (92%)

EXAMPLE 2

Preparation of Crystalline Form D of Perindopril Erbumine

[0064]0.25 g perindopril erbumine form α are suspended in 5 ml of
dichloromethane and the suspension is heated up to 40° C. The
clear solution is cooled in an ice-bath. The colorless crystals are
filtered under reduced pressure (about 10 mbar) and air-dried. Yield:
0.18 g (72%)

EXAMPLE 3

Preparation of Crystalline Form D of Perindopril Erbumine

[0065]0.25 g perindopril erbumine form α are suspended in 12 ml of
acetonitrile and the suspension is heated up to 70° C. The clear
solution is cooled down to room-temperature at a rate of about 10K/h. The
colorless crystals are filtered under reduced pressure (about 10 mbar)
and air-dried. Yield: 0.16 g (64%)

EXAMPLE 4

Preparation of Crystalline Form D of Perindopril Erbumine by
Lyophilization of Perindopril Erbumine Solution

[0066]5% perindopril erbumine solution in water is freezed with liquid
nitrogen. Freeze drying is performed at -20° C. and at a pressure
of about 0.2 mbar over three days.

EXAMPLE 5

Preparation of Crystalline Form D of Perindopril Erbumine

[0067]The dry perindopril erbumine is placed in a mortar and a few drops
of water are added. The mixture is homogenized with a pistil and the
resulting paste is dried at room temperature (20-25° C.) at a
relative humidity below 40%.

EXAMPLE 6

Preparation of Crystalline Form D of Perindopril Erbumine

[0068]0.5 g perindopril erbumine form α are suspended in 5 ml of
t-butylmethyl ether and three drops of water are added. The suspension is
heated up to 40° C. and the clear solution is cooled down to
room-temperature at a rate of about 10K/h. The clear crystals are
filtered under reduced pressure (about 10 mbar) and air-dried. Yield:
0.44 g (88%).

EXAMPLE 7

Preparation of Crystalline Form D of Perindopril Erbumine

[0069]0.5 g perindopril erbumine form α are suspended in 5 ml of
t-butylmethyl ether and three drops of water are added. The suspension is
heated up to 40° C. and the clear solution is quickly cooled to
about 5° C. The clear crystals are filtered under reduced pressure
(about 10 mbar) and air-dried. Yield: 0.46 g (92%).

[0070]Analytical data in examples are achieved by the following hardware:

Infrared Spectroscopy:

[0071]Fourier transform infrared (FTIR) spectra are recorded with a
Brucker IFS 25 spectrometer (Brucker Analytische Messtechnik GmbH,
Karlsruhe, D). Spectra over a range of 4000 to 400 cm-1 with a
resolution of 2 cm-1 (64 scans) are recorded on KBr tablets
(approximately 1.5 mg BD 104 per 275 mg KBr).

[0072]Most of the spectra are recorded with a Durasampler ATR on a
Spectrum GX FT-IR-System spectrometer (Perkin Elmer, Norwalk Conn., USA).
The spectra are recorded over a range of 4000 to 600 cm-1 with a
resolution of 2 cm-1 (24 scans). The analysis is done with Spectrum
v 2.00 software.

Raman-Spectroscopy:

[0073]Raman spectra of the forms are recorded with a Brucker RFS 100 Raman
spectrometer (Bruker Analytische Messtechnik GmbH, Karlsruhe, D),
equipped with a Nd:YAG Laser (1064 nm) as excitation source and a
liquid-nitrogen-cooled, high-sensitivity Ge-detector. The spectra from
3500 to 10 cm-1 are recorded in aluminium sample holders at a laser
power of 300 mW (64 scans per spectrum).

Powder X-Ray Diffraction (PXRD):

[0074]The X-ray diffraction patterns are obtained using a Siemens D-5000
diffractometer (Bruker AXS, Karlsruhe, D) equipped with a theta/theta
goniometer, a CuK.sub.α radiation source, a Goebel mirror (Bruker
AXS, Karlsruhe, D), a 0.15° soller slit collimator and a
scintillation counter. The patterns are recorded at a tube voltage of 40
kV and a tube current of 35 mA, applying a scan rate of 0.005°
2θs-1 in the angular range of 2 to 40° 2θ.

Patent applications by Ulrich Griesser, Axams AT

Patent applications by SANDOZ AG

Patent applications in class Bicyclo ring system having the five-membered hetero ring as one of the cyclos (e.g., octahydroindoles, etc.)

Patent applications in all subclasses Bicyclo ring system having the five-membered hetero ring as one of the cyclos (e.g., octahydroindoles, etc.)